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Affective modulation of anterior cingulate cortex in young
people at increased familial risk of depression

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Affective modulation of anterior cingulate cortex in young
people at increased familial risk of depression

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Please confirm that you accept the terms of use.

Abstract

Background

We previously found that children of parents with depression showed
impaired performance on a task of emotional categorisation.

Aims

To test the hypothesis that children of parents with depression would
show abnormal neural responses in the anterior cingulate cortex, a brain
region involved in the integration of emotional and cognitive
information.

Method

Eighteen young people (mean age 19.8 years) with no personal history of
depression but with a biological parent with a history of major
depression (FH+ participants) and 16 controls (mean age 19.9
years) underwent functional magnetic resonance imaging while completing
an emotional counting Stroop task.

Results

Controls showed significant activation in the pregenual anterior
cingulate cortex to both positive and negative words during the emotional
Stroop task. This activation was absent in FH+
participants.

Conclusions

Our findings show that people at increased familial risk of depression
demonstrate impaired modulation of the anterior cingulate cortex in
response to emotionally valenced stimuli.

Footnotes

Declaration of interest

None.

Funding detailed in Acknowledgement.

In a previous study we found that young people with a parent with depression
who had not had depression themselves (FH+ participants), demonstrated
abnormalities in a task of emotional categorisation,1 suggesting a possible impairment in the integration of emotional and
cognitive information. The anterior cingulate cortex is believed to play an
important role in allocating attentional resources in situations of conflicting
emotional and cognitive demand.2,3 Indeed there is now substantial evidence that the anterior cingulate
cortex has functionally important divisions in which the dorsal ‘cognitive’
region forms part of an attentional network, while the rostral-anterior
‘affective’ region is involved in assessing the salience of emotional and
motivational information.2

It is possible to probe the function of the anterior cingulate cortex in humans
using a modified ‘emotional’ counting Stroop task where emotionally valenced
words compete with the cognitive demands of the task.4 In healthy participants the emotional counting Stroop (ecStroop)
activates the affective subdivision of the anterior cingulate cortex as
measured by functional magnetic resonance imaging (fMRI).4 We therefore tested the hypothesis that, relative to age-matched
controls, FH+ participants would show impaired activation in this subdivision
during performance of the emotional counting Stroop.

Method

Participants and assessments

We recruited 18 young people (9 women, 9 men), mean age 19.8 years (range
19–21) who had never personally had depression but who had a biological
parent with a history of major depression. Potential participants were
assessed with the Structured Clinical Interview for DSM–IV Axis I Disorders
Schedule (SCID–I)5 to exclude a personal current or previous major depression or other
Axis I disorder. The presence of major depression in a parent was assessed
by the family history method using the participant as an informant.6 The criteria used included description of the symptoms of major
depression together with the prescription of specific antidepressant
treatment, either psychotherapy or medication. A history of bipolar disorder
or schizophrenia in a parent was an exclusion criterion. We also recruited
16 controls (10 women, 6 men), mean age 19.9 years (range 18–21) who were
determined by the same instruments to have no current or previous major
depression and no history of depression in a biological parent or other
first-degree relative. All participants were right-handed, according to the
Edinburgh Handedness Inventory,7 and had normal or corrected to normal vision.

Participants were assessed on a number of measures of current emotional
state, including the Mood and Feeling Questionnaire (MFQ),8 the Hospital Anxiety and Depression Scale (HADS)9 and the Perceived Stress Scale (PSS).10 We also administered the Parental Bonding Instrument (PBI)11 and the Life Events Rating Scale (LERS),12 which assesses threat and loss events in the past year and over the
lifespan. All participants gave full informed consent to the study, which
was approved by the local ethics committee.

Emotional counting Stroop task

Participants were scanned while performing a modified version of the
emotional counting Stroop called the ‘name the number of words’ task.4 Word stimuli were a subset drawn from a larger pool used in previous research13 examining depression and anxiety, and selected to be either neutral
(e.g. mileage, molecule), physically threatening (e.g. fatal, accident),
socially threatening (e.g. worthless, inferior) or positive (e.g. generous,
achievement). Physically threatening and socially threatening words were
combined to generate a negative word category. Words were matched for word
length, frequency and imageability. (For further information see online
Table DS1 and www.psy.uwa.edu.au/mrcdatabase/uwa_mrc.htm.)

Participants completed one run of the task with a total of 160 words being
presented across 16 blocks. Four 20-word blocks of each stimulus type were
presented in a pseudo-randomised order and interspersed with 20-s blocks of
fixation, free of stimulus (no motor response) as baseline. Presentation of
the four conditions was counter-balanced across participants and between the
two groups. Participants completed 10 trials during each presentation block
(stimulus presentation 1500 ms, intertrial interval 500 ms). For each trial,
participants viewed between one and four identical words and were instructed
to report (via keypad response) the number of words presented in each trial.
Stimuli were presented on a personal computer using E-Prime (version 1.0;
Psychology Software Tools Inc., Pittsburgh, Philadelphia, USA) and projected
onto an opaque screen at the foot of the scanner bore, which participants
viewed using angled mirrors. Both accuracy and reaction times were recorded
by E-Prime.

Functional MRI data analysis

Functional MRI data were preprocessed and analysed using the functional
magnetic imaging of the Brain Software Library (FSL version 3.3; www.fmrib.ox.ac.uk/fsl), implemented in
Linux SUSE, version 9.1.14 Preprocessing included within-participant image realignment,15 non-brain removal,16 spatial normalisation to a standard template (Montreal Neurological
Institute (MNI) 152 stereotactic template)17 using an affine procedure and spatial smoothing using a Gaussian
kernel (5 mm full-width, half-maximum). The time series in each session was
high pass filtered (to a maximum of 0.007 Hz).

Analyses of data from individual participants were computed using the
general linear model with local autocorrelation correction.18 Three explanatory variables were modelled: ‘neutral’, ‘positive’ and
‘negative’ words. In addition, temporal derivatives were included in the
model as covariates of no interest to increase statistical sensitivity. All
variables were modelled by convolving each block with a haemodynamic
response function, using a variant of a gamma function (i.e. a normalisation
of the probability density function of the gamma function) with a standard
deviation of 3 s and a mean lag of 6 s.

Individual participant data were combined at the group level using full
mixed effects analyses.19 Significant activations were identified using cluster-based
thresholding of statistical images with a height threshold of
Z=2.0 and a (corrected) spatial extent threshold of
P<0.05.20 Approximate Brodmann areas (BA) were identified by transformation of
MNI coordinates into Talairach space (additional information available at
www.mrc-cbu.cam.ac.uk/Imaging).

Results

Participant characteristics and emotional counting Stroop
performance

There were no significant differences between FH+ participants and controls
in age, gender, current mood state, level of perceived stress and experience
of life events. Controls rated their mothers as being more overprotective
(Table 1). Owing to technical
difficulties, accuracy and reaction time data for 8 participants were not
available and the analyses of behavioural data were therefore carried out on
26 individuals (14 FH+ and 12 controls). There were no between-group
differences in accuracy and reaction time (all P>0.40).

Given our a priori hypothesis regarding the role of the
affective subdivision of the anterior cingulate cortex in the emotional
counting Stroop task, we focused subsequent analyses on this brain region.
To examine group×emotion interactions we first extracted percentage signal
change from the significant clusters of this subdivision identified above in
the whole brain analysis (negative v. neutral words and
positive v. neutral words). Further statistical analysis
was implemented using a repeated measures analysis of variance (ANOVA) model
with ‘group’ (FH+ v. controls) as the between-participant
factors (FH+ v. control) and ‘word type’
(positive/negative/neutral words) as the within-participant factor for all
participants. Significant interactions were followed up using simple main
effects (independent and repeated-samples t-tests) to
elicit the degree of this differential activation.

Negative v. neutral word contrast

For this contrast we observed a significant group×word type interaction
(F(1,32)=12.63, P=0.001) extending from the
affective subdivision of the anterior cingulate cortex (BA 24/32)
anteriorly to the medial prefrontal cortex (BA 10). As reported previously,4 controls showed a significantly greater activation to negative
emotional words relative to neutral (repeated-samples t(15)=3.58, P=0.001). By contrast, FH+
participants showed no differential response between neutral and
negatively valenced words (repeated-samples t(15)=1.29, P=0.22). There was a trend for
controls to have a greater deactivation relative to baseline to neutral
words compared with FH+ participants (independent samples
t(32)=1.97, P=0.06) (Fig. 1). Essentially the same findings were obtained
when the negative words were analysed separately as physically
threatening and socially threatening words (data not shown).

Positive v. neutral word contrast

Similar to the negative v. neutral contrast, we observed
a significant group×word type interaction (F(1,32)=12.94, P=0.001) in the affective
subdivision of the anterior cingulate cortex (BA 24/32). As with the
negative words, controls showed a significantly greater BOLD response to
positive words relative to neutral (repeated-samples t(15)=4.31, P=0.001), whereas FH+ participants
had similar responses to neutral and positive word types
(repeated-samples t(17)=0.87, P=0.39). In this comparison the
deactivation from baseline seen in controls following neutral words was
significantly greater than in FH+ participants (independent samples
t(32)=2.35, P=0.03) (Fig. 2). For both positive and negative contrasts
the group by word type interaction remained significant
(P<0.01) when scores on the MFQ were included as a
covariate in the analysis.

Discussion

The main finding of our study is that people at increased familial risk of
depression show altered modulation of the anterior cingulate cortex in an
emotional Stroop task compared with controls. This effect does not seem
attributable to altered task performance. The anterior cingulate cortex is
believed to play a key role in the regulation of emotional and cognitive
processing through appropriate allocation of attentional resources.2,3 Our data therefore suggest that, at a neural level, increased familial
risk of depression is associated with less efficient parallel monitoring of
emotional and cognitive information.

Limitations

An important limitation of the study is that we did not systematically
conduct personal psychiatric interviews with relatives in either FH+ or
control groups and it is therefore possible that some of the parents in the
FH+ group did not have depression or that some parents in the control group
did. Presumably, however, misclassifications of this kind would tend to
decrease rather than increase biological differences between the two groups.
In addition, we have previously shown in a larger study that FH+
participants identified in this way have increased waking salivary cortisol
secretion relative to controls.21 It has been estimated that by young adulthood up to 40% of children
of parents with a clinical mood disorder will have suffered a personal
episode of depression;22 however, the FH+ participants in the current study did not differ
from controls in terms of current affective symptomatology and levels of
perceived stress. In addition, albeit on limited data, it does not appear
that their experience of parental depression is reflected in problems with
parental attachment or in increased life events either recently or over the
life span.

Anterior cingulate cortex activation in controls and FH+
participants

The anterior cingulate cortex has cognitive and affective divisions that are
separable both anatomically and functionally.2 Previous studies in healthy individuals have shown that the affective
division of the anterior cingulate cortex is activated by a number of
emotional manipulations2,23 and our data in healthy participants confirm the findings of Whalen
et al,4 who used an emotional counting Stroop to demonstrate increased
activation in the pregenual region of the affective subdivision of the
anterior cingulate cortex in response to emotional relative to neutral
words. Also, in agreement with Whalen et al, we found that
the emotional counting Stroop task was associated with an overall
deactivation in this subdivision compared with fixation but that the
deactivation was relatively less during presentation of emotional words. It
has been suggested that the overall deactivation of the affective
subdivision of the anterior cingulate cortex in response to the emotional
counting Stroop reflects reciprocal inhibition from the cognitive
subdivision with the purpose of maintaining cognitive performance where
there is increased competition for attentional resources.2,4 Despite this deactivation, the relative increase in activity of the
affective subdivision following presentation of emotional
v. neutral words demonstrates the continuing ability of the
anterior cingulate cortex to monitor emotional information during the
emotional counting Stroop task.

In contrast to these findings in healthy participants, the affective
subdivision of the anterior cingulate cortex in FH+ participants showed no
difference in activation pattern to emotional v. neutral
words. This suggests that in people at increased familial risk of depression
the affective subdivision responds less efficiently to the changing
emotional valence of incoming stimuli. This difference in activation pattern
appeared to be driven partly by the lessened deactivation to neutral words
shown by the FH+ participants. This might imply that in people at increased
familial risk of depression the affective subdivision of the anterior
cingulate cortex reacts to neutral stimuli as if they had an emotional
valence. Whether or not this is the case, our findings suggest that in FH+
people the affective subdivision of the anterior cingulate cortex is less
efficient in detecting differences in the emotional quality of sensory
input.

Changes in anterior cingulate cortex activity in acute
depression

Changes in activity of the anterior cingulate cortex have been reported
frequently in imaging studies of patients who are acutely depressed,
particularly hypoactivity in the cognitive subdivision which may correlate
with impaired performance on cognitive tasks.24,25 Findings in relation to the affective subdivision are more complex.
Wagner et al26 used a counting (non-emotional) Stroop, in conjunction with fMRI, to
study anterior cingulate cortex activity in patients with depression who
were not receiving medication. They found no difference in either task
performance or activation in the cognitive subdivision relative to controls;
however, patients demonstrated less deactivation in the affective
subdivision, a finding rather similar to our own. Other imaging studies in
patients with acute depression have measured activation patterns in the
anterior cingulate cortex in response to tasks involving the processing of
emotional information. Findings have been variable, with some investigations
demonstrating increased neural responses to negative emotional stimuli,
consistent with the emotional biases associated with acute depression.27 However, Elliott et al,28 using an affective go/no-go task, noted findings similar to our own,
namely blunted neural activation to both positive and negative emotional
stimuli in the affective subdivision of the anterior cingulate cortex.

Implications

Our data indicate that abnormalities in the neural response to emotional
stimuli in the anterior cingulate cortex can exist independently of the
presence of acute depression and appear to be present in those at increased
familial risk of illness. The pregenual region of the affective subdivision
of the anterior cingulate cortex, implicated in our study, has connections
to other brain regions known to be involved in emotional experience and
expression, including the orbitofrontal cortex, amygdala, hippocampus and
ventral striatum.25,29 In this respect the pregenual affective subdivision of the anterior
cingulate cortex is well placed to play a key role in the integration of
emotional and cognitive information.2 Hence, abnormalities in this area could be associated with impaired
ability to use emotional information to influence decision-making, as we
observed in an emotional categorisation task in FH+ participants.1 It is possible that deficits of this sort could result in
difficulties in making complex social decisions; this may be one mechanism
through which increased familial risk of depression could be expressed.30

It is important to note that we also observed differential neural
activations to the emotional counting Stroop between FH+ and controls in
brain regions other than the anterior cingulate cortex, including the
thalamus and areas of prefrontal cortex, some of which are known to be
associated with emotional processing. Although many of these brain regions
have connections to the anterior cingulate cortex, these more widespread
changes support the idea of a distributed circuitry underpinning both
emotional processing and the risk of clinical mood disorders.31,32 Hence, vulnerability to depression is likely to be associated with
changes across a network of areas rather than dysfunction solely in the
anterior cingulate cortex. For example, reduced connectivity between
thalamus and anterior cingulate cortex has been demonstrated in patients
with depression compared with healthy controls.33 Future studies investigating temporal correlations between BOLD
response in the anterior cingulate cortex and the prefrontal/limbic regions
reported above are warranted to examine whether altered functional
integration and/or aberrant connectivity pre-date the onset of depression in
at-risk individuals.